Project Summary Induction of normal, but developmentally silenced, fetal globin expression reduces anemia and ameliorates clinical severity in the beta hemoglobinopathies. HDACs 1,2, and 3, are components of the NURD repressor complex, which promotes silencing of fetal globin in adult cells. Prior generation HDAC inhibitors have increased fetal globin in patients, but had limitations for pharmaceutical application and required intermittent administration due to anti-proliferative effects. Cetya has generated a library of high potency HDAC inhibitors, which can be readily modulated in chemical structure, and has demonstrated their efficacy in inducing fetal globin induction in normal human erythroid cells, including a select few candidates which do not shown undesirable growth inhibitory effects at fetal globin inducing concentrations. The laboratory of Dr. Perrine at Boston University will evaluate these candidates in progenitor cells cultured from sickle cell patients. Dr. Perrine has extensive experience in developing treatments for sickle cell and beta thalassemia. This collaboration will explore this new high-potency generation in HDAC chemistry to advance a therapeutic class to the clinic. The studies proposed will identify an optimal HDAC inhibitor for subsequent development to an IND. Aim 1 - To evaluate HDAC inhibitors for magnitude of fetal globin induction and anti- proliferative effects in sickle cell erythroid progenitors and identify an optimal candidate for preclinical development. Aim 2 - To increase the production scale of the selected candidate to support testing in IND-required toxicology studies.